The exact role of graft tissue specific antigens in transplant rejection is unknown. Recently, we have detected CD4+ T cell- and B cell-mediated autoimmunity to cardiac myosin (CM) in murine, porcine, and human recipients of heart transplants. CM is known to initiate autoimmune myocarditis, an autoimmune disease causing cardiac tissue damage and heart failure. Most importantly, we have shown that: 1) pre-transplant sensitization of recipients to CM causes accelerated allograft rejection, 2) induced anti-CM responses are sufficient to trigger rejection of syngeneic heart grafts and 3) modulation of anti-CM responses in recipients results in long-term survival of transplanted hearts. Based on these results, we hypothesize that, in heart-transplanted individuals, the CD4 pathway of alloresponse contributes to acute and/or chronic heart graft rejection by triggering autoimmune responses to CM thereby causing cardiac tissue damages in a fashion similar to that observed in autoimmune myocarditis. To test this hypothesis, the specific aims of the present proposal are to: 1) identify CM determinants and characterize T cells mediating CM autoimmunity post-heart transplantation and, 2) investigate the mechanism(s) by which alloresponse causes autoimmunity to CM in heart-transplanted mice and, and 3) to elucidate the mechanisms by which modulation of anti-CM response can impact the rejection of heart allografts. We anticipate that this knowledge will provide new insights into the mechanisms governing the immune rejection of allotransplants and set the path for the development of new diagnostic tools and selective immune therapies to alleviate graft rejection in clinical transplantation. This award will enhance my career development by allowing me to devote my primary research effort to new transgenic and chimeric mice and a tissue-specific peptide approach for modulation in vivo of anti-graft immunity. This will directly complement my previous training in heart transplantation and enhance my career interest in learning new ways of preventing anti-donor immune reactivity and inducing tissue graft specific tolerance in human clinical organ transplantation.